Synthesis, Monoamine Transporter Binding, Properties, and

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Synthesis, Monoamine Transporter Binding, Properties, and Functional Monoamine Uptake Activity of 3β-[4-Methylphenyl and 4-Chlorophenyl]-2β-[5-(Substituted phenyl)thiazol-2-yl]tropanes Paul K. Gong,† Bruce E. Blough,† Lawrence E. Brieaddy,† Xiaodong Huang,† Michael J. Kuhar,‡ Herna´n A. Navarro,† and F. Ivy Carroll*,† Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, and Yerkes National Primate Center of Emory UniVersity, 954 Gatewood Road NE, Atlanta, Georgia 30329 ReceiVed March 16, 2007

Synthetic methods were developed for the synthesis of the 3β-(4-substituted phenyl)-2β-[5-(substituted phenyl)thiazol-2-yl]tropanes (4a-s). The compounds were evaluated for their monoamine transporter binding and monoamine uptake inhibition properties using both rat brain tissue and cloned transporter assays. In general, the compounds showed higher dopamine transporter (DAT) affinity relative to the serotonin and norepinephrine transporters (SERT and NET, respectively) and greater [3H]dopamine uptake inhibition potency relative to [3H]serotonin and [3H]norepinephrine uptake inhibition. Several compounds were DAT selective relative to the SERT and NET in the monoamine transporter binding assays. The most potent and selective analog in the functional monoamine uptake inhibition test was 3β-(4-methylphenyl-2β-[5-(3-nitrophenyl)thiazol-2-yl]tropane (4p). The neurotransmitter dopamine (DAa) is involved in vital functions such as locomotion, feeding, emotion, and reward.1 Compounds that inhibit binding to the DA transporter (DAT) and, thus, block reuptake of DA have been studied as potential drugs to treat Parkinson’s disease,2-4 attention deficit hyperactivity disorder (ADHD),5,6 depression,7 obesity,8 and cocaine (1) addiction.9 One of the most studied classes of DA uptake inhibitors is the 3-phenyltropanes.10-14 The lead DA uptake inhibitor in this class was 3β-phenyltropane-2β-carboxylic acid methyl ester (2, WIN 35,065-2).15,16 Many WIN 35,065-2 analogs have been synthesized and evaluated for their binding to the DAT.10-14 Replacement of the 2β-carbomethoxy group with certain heterocyclic groups led to analogues that retained high affinity for the DAT and, in some cases, were DAT selective relative to binding at the serotonin and norepinephrine transporters (SERT and NET, respectively).17-19 One of the most interesting compounds is the DAT selective inhibitor 3β-(4chlorophenyl)-2β-[3-(4-methylphenyl)isoxazol-5-yl]tropane (3, RTI-336), which is in advanced preclinical development.17,20-22 Another class of DAT selective 2β-heterocyclic analogues discovered in the initial study of 3β-(aryl)-2β-heterocyclic tropanes was 3β-(4-chlorophenyl)-2β-(5-phenylthiazol-2-yl)tropane (4a, RTI-219).19 In this paper, we describe the synthesis of a number of new 3β-(4-chloro and 4-methylphenyl)-2β-[5(substituted phenyl)thiazol-2-yl]tropanes (4b-s) and report their monoamine transporter binding properties and their functional monoamine uptake inhibition activity.

* To whom correspondence should be addressed. Dr. F. Ivy Carroll, Organic and Medicinal Chemistry, Research Triangle Institute, Post Office Box 12194, Research Triangle Park, NC 27709-2194, Telephone: 919 5416679. Fax: 919 541-8868. E-mail: [email protected]. † Research Triangle Institute. ‡ Yerkes National Primate Center of Emory University. a Abbreviations: DAT, dopamine transporter; SERT, serotonin transporter; NET, norepinephrine transporter; DA, dopamine; 5HT, serotonin; NE, norepinephrine; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOAt, 1-hydroxy-7-azabenzotriazole; HEK, human embryonic kidney.

Chemistry The 4-substituted phenylthiazole analogues 4b-d, 4f, 4h, and 4m were synthesized using a procedure exactly analogous to

10.1021/jm0703035 CCC: $37.00 © 2007 American Chemical Society Published on Web 06/30/2007

2β-Phenylthiazole Analogs of 3β-Phenyltropanes

Scheme 1

that used to prepare 4a (Scheme 1).19 The acid 5a was treated with oxalyl chloride, and the resultant acid chloride was condensed with the appropriate 2-aminoacetophenone to give the amides 6. Cyclization with Lawesson’s reagent gave the 3β-(4-chlorophenyl)-2β-[5-(substituted phenyl)thiazol-2-yl]tropanes (4b-d, 4f, 4h, and 4m). Because the yields obtained by this procedure were low when attempted for the 3β-(4methylphenyl)-2β-[5-(substituted phenyl)thiazol-2-yl]tropane analogs, a new procedure outlined in Scheme 2 was developed. Coupling of 5a or 5b with the appropriately protected aminoacetophenones (12a-h) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 1-hydroxy-7-azabenzotriazole (HOAt) in dimethylformamide afforded the amides (7). Treatment of amides 7 with cold triflic anhydride in the presence of pyridine formed an intermediate imino triflate that, when subjected to an excess of hydrogen sulfide gas, yielded the thioamides 8.23 The thioamides 8 were cyclized to the desired 4e, 4g-l and 4n-s by briefly heating in concentrated hydrochloric acid. The protected aminoacetophenones 12a-h needed to synthesize the amides 7 were produced in a three-step synthesis from commercially available phenacyl bromides 9ah, as outlined in Scheme 3. Heating a solution of 9a-h in dimethylsulfoxide with sodium azide provided the phenacyl azides 10a-h. Treatment of 10a-h with ethylene glycol in chloroform using boron trifluoride etherate as the acid catalyst yielded the ketone-protected phenacyl azides 11a-h. Reduction of the azides 11a-h to the protected 2-aminoacetophenones 12a-h was achieved by first converting the azides 11a-h to the phosphazo intermediate with triphenylphosphine followed by treatment with water (Staudinger reaction24).

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3687

Scheme 2a

a Reagents and conditions: (a) 12a-h, EDCl, HOAt, DMF; (b) (i) Tf O, 2 pyridine, CH2Cl2, -45 to 0 °C, 4 h; (ii) H2S(g), 0 °C, 1 h; (c) (i) 12 N HCl, 60 °C, 30 min; (ii) 3 M NaOH.

Scheme 3a

a Reagents and conditions: (a) NaN , DMSO; (b) HOCH CH OH, 3 2 2 BF3·Et2O, CHCl3; (c) (i) PPh3, THF; (ii) H2O.

Biological Section Target compounds were evaluated in two different monoamine transporter binding assays. In one assay, the striata, midbrain, or frontal cortex of male Sprague-Dawley rats (200-250 g)

were used for competition binding assays at the DAT, SERT, and NET.25,26 The final concentration of radioligands in the assays was 0.5 nM [3H]WIN 35,065-2 for the DAT, 0.2 nM

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Table 1. Monoamine Transporter Binding Properties of 2-Phenylthiazole Analogs Using Rat Brain Tissues

cmpd

Z

WIN 35,065-2 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4n 4o 4p 4q 4r 4s

Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

X

Y

H 4F 4Cl 4Br H NO2 H CH3O Cl CH3O F Cl H NO2 H CH3O Cl CH3O

H H H H Br H NO2 H Cl CH3O H H Br H NO2 H Cl CH3O

DAT, IC50 (nM) [3H]WIN35,428

SERT, Ki (nM) [3H]Paroxetine

NET, Ki (nM) [3H]Nisoxetine

23

1900

920

5.7 6(1 20 ( 3 107 ( 20 18 ( 6 20 ( 3 5(1 14 ( 3 440 ( 100 65 ( 6 12 ( 4 22 ( 3 10 ( 2 41 ( 5 4(1 15 ( 6 102 ( 40 83 ( 20

>2000 371 ( 70 903 ( 320 840 ( 20 280 ( 20 980 ( 100 301 ( 30 800 ( 100 380 ( 30 1510 ( 80 2240 ( 600 1110 ( 70 312 ( 10 1690 ( 240 10,000 >2000 190 ( 20 >2000

8560 >2000 >2000 >2000 >2000 >2000 >2000 >2000 >2000 >2000 >2000 >2000 >2000 >2000 >4300 >2000 >2000 >2000

Table 2. Comparison of Dopamine, Serotonin, and Norepinephrine Transporter Binding and Uptake Studies in C6hDAT, HEK-hSERT, and HEK-hNET Cells for WIN 35,065-2 Analogsa

binding,b Ki (nM)

uptake,b IC50 (nM)

cmpd

Z

X

Y

DAT

SERT

NET

[3H]DA

cocainec 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s

Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

H F Cl Br H NO2 H OCH3 Cl OCH3 F Cl Br H NO2 H OCH3 Cl OCH3

H H H H Br H NO2 H Cl OCH3 H H H Br H NO2 H Cl OCH3

272 ( 60 18 ( 4 12 ( 2 28 ( 3 35 ( 13 39 ( 13 6.1 ( 2.3 7.7 ( 2.1 8.6 ( 2.7 66 ( 8 234 ( 74 61 ( 18 212 ( 10 130 ( 10 12 ( 3 140 ( 40 14 ( 5 53 ( 20 105 ( 47 529 ( 31

601 ( 130 2670 ( 520 653 ( 80 2390 ( 580 5700 ( 1800 1500 ( 500 1820 ( 140 740 ( 110 5200 ( 1900 2710 ( 340 3590 ( 490 1720 ( 600 1320 ( 300 1870 ( 620 870 ( 320 1640 ( 160 580 ( 160 3670 ( 540 2940 ( 340 7710 ( 410

830 ( 147 1840 ( 150 1700 ( 90 2700 ( 400 3290 ( 390 2530 ( 240 2270 ( 380 2510 ( 370 1270 ( 170 2300 ( 70 1910 ( 200 1630 ( 380 2870 ( 190 4240 ( 970 2210 ( 300 1970 ( 660 990 ( 140 3630 ( 810 >6100 1390 ( 300

267 ( 47 158 ( 63 30 ( 6 41 ( 10 107 ( 22 63 ( 28 30 ( 5 45 ( 11 38 ( 18 416 ( 82 212 ( 85 181 ( 28 400 ( 100 810 ( 290 98 ( 11 197 ( 54 23 ( 5 226 ( 77 469 ( 77 885 ( 57

[3H]5HT

[3H]NE

318 ( 57 2710 ( 500 1010 ( 200 4400 ( 900 8220 ( 830 4000 ( 1000 3600 ( 600 1610 ( 470 6700 ( 700 5300 ( 1700 >6800 3200 ( 1300 377 ( 90 1840 ( 500 3860 ( 500 3170 ( 800 2380 ( 190 6800 ( 1800 4400 ( 1100 >10 000

385 ( 40 750 ( 270 690 ( 190 912 ( 40 960 ( 300 2300 ( 200 582 ( 94 650 ( 160 620 ( 130 6500 ( 1000 4210 ( 170 4870 ( 840 1170 ( 60 1820 ( 410 3240 ( 280 1550 ( 210 2040 ( 240 1810 ( 380 4000 ( 2000 >6900

a This data was supplied by the NIDA-CTDP program. Details of experimentals for these binding and uptake studies are given in ref 27. b Values for the mean ( standard error of three independent experiments, each conducted with triplicate determination. c Data taken from ref 27.

[3H]paroxetine for the SERT, and 0.5 nM [3H]nisoxetine for the NET. Results from this assay are listed in Table 1. In the second assay, the competition binding assays were determined using (h)DAT, (h)SERT, and (h)NET, stably expressed in

HEK293 cells, and the nonselective radioligand [125I]RTI-55 for the analogues 4b-s (Table 2).27 The HEK-(h)DAT, -(h)SERT, and -(h)NET cells were also used to evaluate the compound’s ability to block the reuptake of [3H]dopamine ([3H]-


DA), [3H]serotonin ([3H]5HT), and [3H]norepinephrine ([3H]NE; Table 2).27 Results and Discussion In our original studies of 3β-phenyl-2β-heterocyclic tropane analogs, we reported that the 2β-phenylthiazole 4a could be easily synthesized using standard methods for preparing thiazoles. Specifically, the 3β-(4-chlorophenyl)tropane-2β-(Nphenacyl)-carboxamide was easily prepared and cyclized to the desired 4a in good yield by using Lawesson’s reagent. We anticipated that the aromatic substituted analogs 4b-s could be prepared by a similar procedure and, indeed, we were able to obtain the 3β-(4-chlorophenyl) analogs 4b-d, 4f, and 4h in satisfactory yield (Scheme 1). Surprisingly, when we tried this procedure on the 3β-(4-methylphenyl) analogs, the reactions became much more difficult to workup and the yields were unacceptable. Fortunately, we were able to develop a new synthesis of this class of compounds, which proceeded with much less difficulty and higher overall yields (Scheme 2). The key step in the new synthetic route was the conversion of the amides 7 to the thioamides 8. This was achieved by first converting amide 7 to the triflate enolate, followed by treatment with hydrogen sulfide. Attempts to convert 7 to 8 using Lawesson’s reagent, or phosphorus pentasulfide under a variety of conditions, including different solvents, were unsuccessful. Once the thioamides 8 were in hand, they were easily converted to the desired 2β-arylthiazole analogs by acid-catalyzed cyclization. The 2β-arylthiazole analogs were evaluated for their monoamine transporter binding properties using rat brain tissue (Table 1) or cloned receptors (Table 2). All compounds tested, with the exception of the 3β-(4-chlorophenyl)-2β-(3,4-dichlorophenyl)thiazole analog 4i, in the rat tissue assay had higher affinity for the DAT relative to the SERT and NET. With a few exceptions, the 2β-arylthiazole analogs tended to show lower IC50s for the DAT in the rat brain tissues test than the Kis for the DAT in the cloned receptor assay. An analysis of the DAT affinities in Table 1 shows that 11 of the analogs evaluated in the rat brain DAT test had IC50s of 20 nM or less. The rank order for these analogs is: 4p > 4g > 4a > 4b > 4n > 4k > 4h > 4q > 4e > 4c ) 4f. A similar analysis of the DAT affinities determined using cloned human transporters (Table 2) shows that seven of the same analogs had Kis of 20 nM or less, although their rank order was different: 4f > 4g > 4h > 4n ) 4b > 4p > 4a. These results show that the highest potency compounds were identified by either the rat brain tissue or the cloned receptor assays. The two most potent compounds in the rat brain tissue DAT test are the 3β-(4-methyl and 3β-4chlorophenyl)-2β-(3-nitrophenyl)thiazole analogs 4p and 4g, which have IC50s of 4 and 5 nM, respectively. In the case of the cloned transporter test, the 3β-(4-chlorophenyl)-2β-(4nitrophenyl) and (4-methoxyphenyl)thiazole analogs 4f and 4g with Ki of 6.1 and 7.7 nM, respectively, possessed the highest affinity. Similar to the radioligand binding data, all of the compounds 4a-s were better uptake inhibitors at the (h)DAT relative to the (h)SERT and (h)NET (Table 2). Even though the rank order of potency in [3H]DA uptake inhibition did not parallel the rank order in the DAT binding studies, the three most potent analogs, all of which showed IC50s of less than 30 nM, are also the three analogs possessing the highest DAT affinity. The most potent analog in the [3H]DA uptake inhibition study was the 3β-(4methylphenyl)2β-(3-nitrophenyl)thiazole analog 4p, with an IC50 of 23 nM. The rank order of the four most potent analogs is 4p


> 4b ) 4f > 4h. Thus, for determining activity at the DAT, binding or uptake yields comparable results. The most DAT selective analog relative to SERT in the cloned receptor assay was the 3β-(4-chlorophenyl)-2β-(4methoxyphenyl)thiazole analog 4h, which showed a 600-fold preference for the DAT. The 3β-(4-chlorophenyl)-2β-(4-nitrophenyl)thiazole analog 4f showed a 370-fold preference for the DAT relative to the NET and, thus, was the most DAT selective analog relative to the NET. In the monoamine uptake inhibition studies, the 3β-(4-chlorophenyl)-2β-(4-nitrophenyl)thiazole 4f and the 3β-(4-methylphenyl)-2β-(3-nitrophenyl)thiazole 4p both had greater than 100-fold selectivity for [3H]DA uptake inhibition relative to [3H]5HT inhibition. Analog 4p also had 88fold selectivity for [3H]DA uptake inhibition relative to [3H]NE uptake inhibition, whereas 4f possessed only a 19-fold selectivity for [3H]DA uptake inhibition. Analog 4p was also highly selective in the rat brain tissue binding assay showing 2400and 1000-fold selectivity for the DAT relative to the SERT and NET. In summary, using the 3β-(4-chlorophenyl)-2β-phenylthiazole analog 4a as a lead compound, a number of analogs were designed, synthesized, and evaluated for their monoamine transporter binding and monoamine uptake inhibition properties to gain a better understanding of the structure-activity relationship (SAR) for this class of compounds. While most of the 3β(4-chlorophenyl)-2β-(substituted phenyl)thiazole analogs could be synthesized by standard methods used for the synthesis of thiazoles, a new method had to be developed to synthesize the 3β-(4-methylphenyl)-2β-(substituted phenyl)thiazole analogs. The key step in the synthesis was the conversion of an amide to the thioamide that could be cyclized to the desired target compounds. In general, the compounds showed higher DAT affinity relative to the SERT and NET and greater [3H]DA uptake inhibition potency relative to [3H]5HT and [3H]NE uptake inhibition. Based on the functional monoamine uptake data, the most potent and DA selective ligand was the 3β-(4methylphenyl)-2β-(3-nitrophenyl)thiazole analog 4p. However, based on the monoamine transporter binding data, several other compounds were DAT selective relative to the SERT and NET. These compounds should not be overlooked as potential DAT selective compounds, because it is difficult to predict the pharmacokinetic and pharmacodynamic properties of compounds. Experimental Section Nuclear magnetic resonance (1H NMR and 13C NMR) spectra were recorded on a 300 MHz (Bruker AVANCE 300) spectrometer. Chemical shift data for the proton resonances were reported in parts per million (δ) relative to internal (CH3)4Si (δ 0.0). Optical rotations were measured on an AutoPol III polarimeter purchased from Rudolf Research. Elemental analyses were performed by Atlantic Microlab, Norcross, GA. Analytical thin-layer chromatography (TLC) was carried out on plates precoated with silica gel GHLF (250 µM thickness). TLC visualization was accomplished with a UV lamp or in an iodine chamber. All moisture-sensitive reactions were performed under a positive pressure of nitrogen maintained by a direct line from a nitrogen source. Anhydrous solvents and hydrogen sulfide gas were purchased from Aldrich Chemical Co. 3β-(4-Chlorophenyl)-2β-[5-(4-chlorophenyl)thiazol-2-yl]tropane (4c) Hydrochloride. To compound 5a (3.0 g, 0.0107 mol) in CH2Cl2 (75 mL) was added oxalyl chloride (11.0 mL, 2 M in CH2Cl2, 0.0214 mol). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The resulting acid chloride was redissolved in CH2Cl2 (50 mL), and 2-amino-4′-chloroacetophenone hydrochloride (4.93 g, 0.0239 mol) was added, followed by Et3N (5.47 g, 0.0541 mol) in CH2Cl2 (50 mL). The reaction mixture was stirred at rt overnight, filtered, and concentrated in vacuo to afford

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5.9 g of a red-orange amorphous solid, which was purified by column chromatography on silica gel, eluting with CH2Cl2CHCl3-MeOH-NH4OH (50:40:9:1) to yield 3.7 g (80%) of 6c as an orange amorphous solid. Compound 6c (3.7 g, 0.0086 mol) and Lawesson’s reagent (13.9 g, 0.034 mol) were added to toluene (150 mL) and stirred at reflux for 6 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with hexane-Et2O-Et3N (10:9:1) to afford 1.28 g (35%) of 4c as a white solid. The free base was dissolved in CH2Cl2 and treated with excess 2 M ethereal HCl. The mixture was concentrated and triturated with warm EtOAc, cooled, and filtered to yield 0.80 g of 4c‚HCl as a white solid: mp 142-143 °C; 1H NMR (CDCl3, free base) δ 7.57 (s, 1H), 7.51 (d, 2H), 7.34 (d, 2H), 7.08 (d, 2H), 6.80 (d, 2H), 3.50 (bd, 1H), 3.40 (bs, 1H), 3.20-3.53 (m, 2H), 2.55 (q, 1H), 2.10-2.42 (m, 2H), 2.35 (s, 3H), 1.57-1.90 (m, 3H); [R]D ) -25.3° (c 0.53, MeOH). Anal. (C23H23Cl3N2S‚2H2O) C, H, N, S. 3β-(4-Chlorophenyl)-2β-[5-(4-fluorophenyl)thiazol-2-yl]tropane (4b) Hydrochloride. Compound 4b was prepared by a procedure analogous to that described for the preparation of 4c to afford 23% of 4b as a beige solid: mp (HCl salt) 188-190 °C; 1H NMR (CDCl3, free base) δ 7.53 (m, 3H), 7.08 (m, 4H), 6.80 (d, 2H), 3.50 (bd, 1H), 3.40 (bs, 1H), 3.23-3.40 (m, 2H), 2.65 (bs, 1H), 2.10-2.42 (m, 2H), 2.35 (s, 3H), 1.60-1.85 (m, 3H); [R]D ) -24.0° (c 0.47, MeOH). Anal. (C23H23Cl2FN2S‚0.5H2O) C, H, N. 3β-(4-Chlorophenyl)-2β-[5-(4-bromophenyl)thiazol-2-yl]tropane (4d) Hydrochloride. Compound 4d was prepared by a procedure analogous to that described for 4c to give 32% of 4d as a white solid: mp (HCl salt) 114-116 °C; 1H NMR (CDCl3, free base) δ 7.60 (s, 1H), 7.46 (q, 4H), 7.08 (d, 2H), 6.80 (d, 2H), 3.50 (bd, 1H), 3.40 (bs, 1H), 3.24-3.42 (m, 2H), 2.30-2.42 (m, 2H), 2.35 (s, 3H), 1.65-1.85 (m, 3H); [R]D -25.9° (c 0.78, MeOH). Anal. (C23H24Cl3BrN2S‚H2O) C, H, N, S. 3β-(4-Chlorophenyl)-2β-[5-(4-nitrophenyl)thiazol-2-yl]tropane (4f) Hydrochloride. Compound 4f was prepared by a procedure analogous to that described for 4c to give 23% of 4f as a light yellow solid: mp (HCl salt) 180-183 °C; 1H NMR (CDCl3, free base) δ 8.24 (d, 2H), 7.71 (m, 3H), 7.10 (d, 2H), 6.82 (d, 2H), 3.55 (bd, 1H), 3.42 (bs, 1H), 3.27-3.41 (m, 2H), 2.22-2.40 (m, 2H), 2.37 (s, 3H), 1.63-1.87 (m, 3H); [R]D -23.7° (c 0.38, MeOH). Anal. (C23H23Cl2N3O2S‚1.75H2O) C, H, N, S. 3β-(4-Chlorophenyl)-2β-[5-(4-methoxyphenyl)thiazol-2-yl]tropane (4h) Hydrochloride. Compound 4h was prepared by a procedure analogous to that described for 4c to give 35% of 4h as a beige solid: 1H NMR (CDCl3 free base) δ 7.50 (d, 2H J ) 8.7 Hz), 7.49 (s, 1H), 7.08 (d, 2H, J ) 8.5 Hz), 6.91 (d, 2H, J ) 8.7 Hz), 6.82 (d, 2H, J ) 8.5 Hz), 3.83 (s, 3H), 3.49 (m, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 3.24 (m, 1H), 2.34 (s, 3H), 2.17-2.44 (m, 2H), 1.82 (m, 2H), 1.63 (m, 2H); 13C NMR (CDCl3) δ 168.1, 159.3, 140.4, 139.7, 135.2, 131.9, 129.1, 128.1, 127.9, 125.2, 114.3, 65.8, 61.6, 55.4, 52.9, 41.7, 36.9, 35.1, 26.0, 25.5; mp (HCl salt) 171173 °C; [R]D -16.4° (c 0.75, MeOH). Anal. (C24H27Cl2N2OS‚2HCl) C, H, N, S. 3β-(4-Methylphenyl)-2β-[5-(4-bromophenyl)thiazol-2-yl]tropane (4m) Tartrate. Compound 4m was prepared by a procedure analogous to that described for 4c except the compound was characterized as the tartrate salt: mp 190-193 °C, [R]D20 -21.1 (c 0.5, CH3OH); 1H NMR (CDCl3 free base) δ 7.58 (s, 1H), 7.49 (d, 2H, J ) 8.8 Hz), 7.44 (d, 2H, J ) 8.8 Hz), 6.93 (d, 2H, J ) 7.9 Hz), 6.76 (d, 2H, J ) 8.0 Hz), 3.51 (m, 1H), 3.49 (m, 1H), 3.31 (m, 1H), 3.23 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.15-2.45 (m, 2H), 1.84 (m, 2H), 1.63 (m, 2H); 13C NMR (CDCl3) δ 170.0, 138.6, 138.5, 136.5, 135.7, 131.9, 131.6, 128.8, 127.9, 127.5, 121.3, 65.8, 61.8, 53.1, 41.7, 37.0, 35.1, 26.0, 25.6, 21.0. Anal. (C28H32BrN206‚ 2.5H2O) C, H, N. 4-Nitrophenacyl Azide (10c). Into a 100-mL round-bottom flask was added 950 mg (3.9 mmol) of 4-nitrophenacyl bromide, 271 mg (4.3 mmol) of sodium azide, and 15 mL of DMSO. The reaction mixture was allowed to stir at room temperature for at least 30 min, 50 mL of ice water was added, and the aqueous layer was

Gong et al.

extracted with 125 mL of diethyl ether. The combined organic layers were washed with water and brine and dried with Na2CO3. The organic fractions were concentrated to a residue that was purified by flash chromatography using CH2Cl2 as the eluent to give 700 mg (87%) of 10c as a slightly yellow powder: 1H NMR (CDCl3) δ 8.35 (d, 2H, J ) 9 Hz), 8.10 (d, 2H, J ) 9 Hz), 4.61 (s, 2H). 4-Fluorophenacyl Azide (10a). Using a procedure similar to that described for 10c, 1.7 g (0.0078 mol) of 4-fluorophenacyl bromide was treated with NaN3 to give 1.24 g (88%) of 10a as yellow crystals: 1H NMR (CDCl3) δ 7.95 (m, 2H), 7.18 (m, 2H), 4.53 (s, 2H). 4-Chlorophenacyl Azide (10b). Using a procedure similar to that described for 10c, 25 g (0.11 mol) of 4′-chlorophenacyl bromide was treated with NaN3 to give 10.5 g (50%) of 10b as a white solid: 1H NMR (CDCl3) δ 7.85 (d, 2H, J ) 8.7 Hz), 7.49 (d, 2H, J ) 8.7 Hz), 4.53 (s, 2H). 4-Methoxyphenacyl Azide (10d). Using a procedure similar to that described for 10c, 5.26 g (0.023 mol) of 4-methoxyphenacyl bromide was treated with sodium azide to give 4.1 g (93%) of 10d as a light yellow powder: 1H NMR (CDCl3) δ 7.89 (d, 2H, J ) 7.2 Hz), 6.96 (d, 2H, J ) 7.2 Hz), 4.54 (s, 2H), 3.89 (s, 3H). 3-Bromophenacyl Azide (10e). Using a procedure similar to that described for 10c, 2.2 g (0.008 mol) of 3-bromophenacyl bromide was treated with sodium azide to give 1.3 g (62%) of 10e as a white powder: 1H NMR (CDCl3) δ 8.05 (m, 1H), 7.84 (d, 1H, J ) 7.5 Hz), 7.77 (d, 1H), 7.37 (dd, 1H), 4.54 (s, 2H). 3-Nitrophenacyl Azide (10f). Using a procedure similar to that described for 10c, 3.16 g (0.013 mol) of 3-nitrophenacyl bromide was treated with NaN3 to give 1.80 g (68%) of 10f as a yellow powder: 1H NMR (CDCl3) δ 8.74 (d, 1H, J ) 1.8 Hz), 8.49 (dd, 1H, J ) 8.1 Hz), 8.27 (d, 1H, J ) 8.1 Hz), 7.75 (dd, 1H J ) 8.1 Hz), 4.63 (s, 1H). 3,4-Dichlorophenacyl Azide (10g). Using a procedure similar to that described for 10c, 2.14 g (0.008 mol) of 3,4-dichlorophenacyl bromide was treated with NaN3 to give 881 mg (48%) of 10g as a clear oil: 1H NMR (CDCl3) δ 8.00 (d, 1H, J ) 1.8 Hz), 7.73 (dd, 1H, J ) 8.4 Hz), 7.59 (d, 1H, J ) 8.1 Hz), 4.52 (s, 2H). 3,4-Dimethoxyphenacyl Azide (10h). Using a procedure similar to that described for 10c, 11.1 g (0.043 mol) of 3,4-dimethoxyphenacyl bromide was treated with NaN3 to give 8.29 g (87%) of 10h as a yellow powder: 1H NMR (CDCl3) δ 7.52 (d, 1H, J ) 2.1 Hz), 7.47 (dd, 1H, J ) 8.4 Hz), 6.89 (d, 1H, J ) 8.4 Hz), 4.53 (s, 2H), 3.96 (s, 3H), 3.95 (s, 3H). 4-Nitrophenacyl Azide Ethylene Ketal (11c). A solution of 473 mg (2.29 mmol) of 10c, 2.3 mL (41.3 mmol) of ethylene glycol, and 3 mL (23.4 mmol) of BF3‚Et2O in 20 mL of CH2Cl2 was allowed to stir for 2 days under a N2 atmosphere at room temperature. Saturated NaHCO3 solution was added, and the mixture was extracted with CHCl3. The extracts were washed with water and brine and then dried (Na2SO4). Organic layers were concentrated to dryness to leave a residue that was purified by silica gel chromatography, eluting with a 0-25% EtOAc/hexanes gradient. Concentration of collected fractions yielded 395 mg (69%) of 11c as white feathery crystals: 1H NMR (CDCl3) δ 8.23 (d, 2H, J ) 8.7 Hz), 7.70 (d, 2H, J ) 8.7 Hz), 4.22 (m, 2H), 3.92 (m, 2H), 3.46 (s, 2H). 4-Fluorophenacyl Azide Ethylene Ketal (11a). Using a procedure similar to that described for 11c, 1.22 g (0.007 mol) of 10a was converted to 1.33 g (87%) of 11a as a clear oil: 1H NMR (CDCl3) δ 7.48 (m, 2H), 7.05 (m, 2H), 4.18 (m, 2H), 3.90 (m, 2H), 3.42 (s, 2H). 4-Chlorophenacyl Azide Ethylene Ketal (11b). Using a procedure similar to that described for 11c, 10.5 g (0.054 mol) of 10b was converted to 6.2 g (54%) of 11b as a white solid: 1H NMR (CDCl3) δ 7.44 (d, 2H, J ) 8.4 Hz), 7.34 (d, 2H, J ) 8.4 Hz), 4.17 (m, 2H), 3.89 (m, 2H), 3.41 (s, 2H). 4-Methoxyphenacyl Azide Ethylene Ketal (11d). Using a procedure similar to that described for 11c, 1.53 g (0.008 mol) of 10d was converted to 1.32 g (70%) of 11d as a clear oil that solidified to a white solid upon standing: 1H NMR (CDCl3) δ 7.42


(d, 2H, J ) 7.2 Hz), 6.88 (d, 2H, J ) 7.2 Hz), 4.15 (m, 2H), 3.90 (m, 2H), 3.81 (s, 3H), 3.42 (s, 2H). 3-Bromophenacyl Azide Ethylene Ketal (11e). Using a procedure similar to that described for 11c, 980 mg (4.1 mmol) of 10e was converted to 923 mg (80%) of 11e as a clear oil: 1H NMR (CDCl3) δ 7.66 (m, 1H), 7.46 (m, 2H), 7.25 (m, 1H), 4.18 (m, 2H), 3.90 (m, 2H), 3.41 (s, 2H). 3-Nitrophenacyl Azide Ethylene Ketal (11f). Using a procedure similar to that described for 11c, 1.65 g (0.008 mol) of 10f was converted to 1.29 g (64%) of 11f as a yellow oil that solidified upon standing: 1H NMR (CDCl3) δ 8.39 (d, 1H, J ) 1.8 Hz), 8.22 (dd, 2H, J ) 8.1 Hz), 7.83 (d, 1H, J ) 1.8 Hz), 7.58 (dd, 1H, J ) 1.8 Hz), 4.23 (m, 2H), 3.93 (m, 2H), 4.46 (s, 2H). 3,4-Dichlorophenacyl Azide Ethylene Ketal (11g). Using a procedure similar to that described for 11c, 720 mg (3.13 mmol) of 10g was converted to 606 mg (71%) of 11g as a clear oil: 1H NMR (CDCl3) δ 7.60 (d, 1H, J ) 2.1 Hz), 7.45 (d, 1H, J ) 8.4 Hz), 7.32 (d, 1H, J ) 9 Hz), 4.18 (m, 2H), 3.90 (m, 2H), 3.41 (s, 2H). 3,4-Dimethoxyphenacyl Azide Ethylene Ketal (11h). Using a procedure similar to that described for 11c, 7.97 g (0.036 mol) of 10h was converted to 7.6 g (80%) of 11h as a white powder: 1H NMR (CDCl3) δ 7.06 (dd, 1H, J ) 8.1 Hz), 7.01 (d, 1H, J ) 1.8 Hz), 6.89 (d, 1H, J ) 8.1 Hz), 4.17 (m, 2H), 3.92 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.43 (s, 2H). 4-Nitrophenacylamine Ethylene Ketal (12c). A solution of 1.20 g (0.0048 mol) of 11c was stirred with 1.36 g (0.0053 mol) of PPh3 in 75 mL of dry THF for 1 day. The reaction mixture was concentrated to 10 mL, ∼150 µL of water (an excess) was added, and the reaction mixture was allowed to stir overnight. The reaction mixture was evaporated to dryness, and the resulting residue was purified by flash chromatography on silica gel using 0-25% CMA gradient solution in CH2Cl2 (where CMA refers to 80:18:2 ratio of CHCl3/MeOH/NH4OH elution solvent). Isolated fractions provided 804 mg (75%) of 12c as a pure, slightly yellow powder: 1H NMR (CDCl3) δ 8.21 (d, 1H, J ) 7.2 Hz), 7.65 (d, 1H, J ) 7.2 Hz), 4.11 (m, 2H), 3.84 (m, 2H), 2.92 (s, 2H), 1.39 (bs, 2H). 4-Fluorophenacylamine Ethylene Ketal (12a). Using a procedure similar to that described for 12c, 1.32 g (0.006 mol) of 11a was reduced to give 847 mg (73%) of 12a as a clear oil: 1H NMR (CDCl3) δ 7.42 (m, 2H), 7.3 (m, 2H), 4.05 (m, 2H), 3.84 (m, 2H), 2.89 (s, 2H), 1.40 (bs, 2H). 4-Chlorophenacylamine Ethylene Ketal (12b). Using a procedure similar to that described for 12c, 10.5 g (0.054 mol) of 11b was reduced to give 6.06 g (54%) of 12b as a white solid: 1H NMR (CDCl3) δ 7.44 (d, 2H, J ) 8.4 Hz), 7.34 (d, 2H, J ) 8.4 Hz), 4.17 (m, 2H), 3.89 (m, 2H), 3.41 (s, 2H), 1.34 (bs, 2H). 4-Methoxyphenacylamine Ethylene Ketal (12d). Using a procedure similar to that described for 12c, 1.13 g (0.0048 mol) of 11d was reduced to give 617 mg (61%) of 12d as a white waxy solid: 1H NMR (CDCl3) δ 7.37 (d, 2H, J ) 8.7 Hz), 6.88 (d, 2H, J ) 8.7 Hz), 4.05 (m, 2H), 3.85 (m, 2H), 3.80 (s, 3H), 2.90 (s, 2H), 1.38 (bs, 2H). 3-Bromophenacylamine Ethylene Ketal (12e). Using a procedure similar to that described for 12c, 923 mg (3.25 mmol) of 11e was reduced to give 793 mg (95%) of 12e as a clear oil: 1H NMR (CDCl3) δ 7.61 (m, 2H), 7.43 (d, 1H), 7.38 (d, 1H), 7.21 (dd, 1H), 4.07 (m, 2H), 3.84 (m, 2H), 2.89 (s, 2H), 1.37 (bs, 2H). 3-Nitrophenacylamine Ethylene Ketal (12f). Using a procedure similar to that described for 12c, 1.10 g (0.0042 mol) of 11f was reduced to give 593 mg (60%) of 12f as a white solid: 1H NMR (CDCl3) δ 8.34 (dd, 1H, J ) 1.8 Hz), 8.19 (dd, 1H, J ) 8.1 Hz), 7.80 (d, 1H, J ) 8.1 Hz), 7.55 (dd, 1H, J ) 8.1 Hz), 4.13 (m, 2H), 3.86 (m, 2H), 2.94 (s, 2H), 1.40 (bs, 2H). 3,4-Dichlorophenacylamine Ethylene Ketal (12g). Using a procedure similar to that described for 12c, 606 mg (2.21 mmol) of 11g was reduced to give 522 mg (95%) of 12g as a clear oil: 1H NMR (CDCl ) δ 7.55 (d, 1H, J ) 1.8 Hz), 7.42 (d, 1H, J ) 8.1 3 Hz), 7.27 (d, 1H, J ) 8.4 Hz), 4.07 (m, 2H), 3.84 (m, 2H), 2.81 (s, 2H), 1.35 (bs, 2H). 3,4-Dimethoxyphenacylamine Ethylene Ketal (12h). Using a procedure similar to that described for 12c, 6.63 g (0.025 mol) of


11h was reduced to give 5.1 g (85%) of 12h as a white powder: 1H NMR (CDCl ) δ 7.01 (dd, 1H, J ) 8.1 Hz), 6.97 (d, 1H), 6.85 3 (d, 1H), 4.07 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86 (m, 2H), 2.92 (s, 2H), 1.34 (bs, 2H). 3β-(4-Methylphenyl)tropane-2β-N-4′-fluorophenacylcarboxamide Ethylene Ketal (7k). To a cooled solution (0 °C) of 260 mg (1 mmol) of 5b and 198 mg (1 mmol) of 12a in dry DMF was added 6 mL of a 3 M (1.8 mmol) HOAt followed by 650 mg (3.4 mmol) of EDCI. After stirring 2 days under N2 at 25 °C, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel using 25-50% CMA solvent in CH2Cl2 as the eluent. Isolated fractions produced 341 mg (78%) of 7k as a pure white solid: 1H NMR (CDCl3) δ 9.86 (bt, 1H), 7.53 (dd, 2H), 7.07-6.96 (m, 6H), 4.11 (m, 2H), 3.91 (m, 2H), 3.59 (m, 2H), 3.23 (t, 2H), 3.05 (m, 1H), 2.45 (dd, 1H), 2.26 (s, 3H), 2.20 (s, 3H), 2.14 (m, 3H), 1.72-1.56 (m, 3H); 13C NMR (CDCl3) δ 129.3, 128.3, 128.0, 115.4, 65.5, 65.3, 64.3, 61.8, 54.9, 46.7, 41.5, 36.1, 35.6, 26.5, 25.4, 21.5; LCMS (ESI) m/z 439.7 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-4′-fluorophenacylcarboxthioamide (8k). To a chilled (dry ice/acetonitrile) solution of 294 mg (0.67 mmol) of 7k in 7 mL of CH2Cl2 containing 190 µL (2.38 mmol) of pyridine under N2 was added 140 µL (0.84 mmol) of Tf2O. The reaction mixture was slowly warmed to 0 °C and allowed to stir for 4 h in an ice bath. Hydrogen sulfide gas was bubbled through the solution. The reaction mixture was diluted with EtOAc, washed with NaHCO3 solution, water, and brine, and dried (Na2SO4). The organic fractions were concentrated to dryness, and the residue was subjected to column chromatography on silica gel using 25-50% CMA solution in CH2Cl2 gradient. Recrystallization of dried product fractions from EtOAc/heptanes afforded 200 mg (66%) of 8k as a tan solid: 1H NMR (CDCl3) δ 12.21 (bs, 1H), 7.56 (dd, 2H), 7.08 (dd, 2H, J ) 8.1 Hz), 7.03 (d, 2H, J ) 8.1 Hz), 6.92 (d, 2H, J ) 8.1 Hz), 4.17 (m, 2H), 3.95 (m, 2H), 3.95 (d, 1H), 3.77 (d, 1H), 3.44 (d, 1H), 3.28 (m, 1H), 3.20 (d, 1H), 3.10 (m, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.19 (m, 3H), 1.75 (m, 2H), 1.61 (dt, 1H); LCMS (ESI) m/z 455.4 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(4′-fluorophenyl)thiazol-2-yl]tropane (4k) Hydrochloride. A solution of 155 mg (0.354 mmol) of 8k dissolved in 3 mL of 12 N HCl was heated to 65 °C for 0.5 h in a hot water bath. Ice was added directly to the solution, and the mixture was basified with 12 mL of 3 N NaOH. The basified solution was extracted with 3 × 25 mL EtOAc, and the combined organic layers were washed with saturated NaHCO3, water, and brine and dried (Na2SO4). Solvent was evaporated to yield 122 mg (88%) of yellowish solid. To a solution of 53 mg (0.135 mol) of the solid in 2 mL of dry CHCl3 was added an excess amount (3 to 6 equiv) of 1 M HCl in ether. The acidified solution was concentrated to remove any excess solvent and HCl. The final residue was washed once with dry diethyl ether and dried to give 48 mg (81%) of the hydrochloride salt of 4k as a light tan solid: 1H NMR (CDCl free base) δ 7.52 (m, 3H), 7.06 (dd, 2H, J ) 6.9 3 Hz), 6.92 (d, 1H, J ) 8.1 Hz), 6.77 (d, 2H, J ) 8.1 Hz), 3.50 (d, 1H), 3.38 (m, 1H), 3.29 (t, 1H), 3.25 (t, 1H), 2.38 (m, 1H), 2.34 (s, 3H), 2.24 (m, 2H), 2.21 (s, 3H), 1.83 (q, 2H), 1.62 (dt, 1H); 13C NMR (CDCl3) δ 136.40, 129.18, 128.57, 127.97, 116.32, 66.25, 62.16, 53.56, 42.16, 37.42, 35.58, 26.41, 25.98, 21.40; LCMS (ESI) m/z 393.7 (M + 1)+. The hydrochloride salt had a mp of 220222 °C; [R]20D -18.5° (c 0.20, CH3OH). Anal. (C24H27ClFN2S‚ 0.5H2O) C, H, N, S. 3β-(4-Methylphenyl)tropane-2β-N-4′-chlorophenacylcarboxamide Ethylene Ketal (7l). Using a procedure similar to that described for 7k, 2.82 g (0.011 mol) of 5b was coupled with 2.34 g (0.011 mol) of 12b to give 3.24 g (65%) of 7l as a white powder: 1H NMR (CDCl3) δ 9.87 (bt, 1H), 7.47 (d, 2H, J ) 8.4 Hz), 7.34 (d, 2H, J ) 8.4 Hz), 7.02 (d, 2H, J ) 8.1 Hz), 6.96 (d, 2H, J ) 8.1 Hz), 4.10 (m, 2H), 3.90 (m, 2H), 3.58 (d, 2H, J ) 5.1 Hz), 3.24 (m, 2H), 3.03 (m, 1H), 2.45 (d, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.14 (m, 3H), 1.75-1.55 (m, 3H); 13C NMR (CDCl3) δ

3692


129.34, 128.76, 128.01, 65.51, 65.32, 64.32, 61.85, 54.84, 46.58, 41.49, 36.03, 35.60, 26.51, 25.37, 21.50; LCMS (ESI) m/z 456.1 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-4-chlorophenacylcarboxthioamide Ethylene Ketal (8l). Using a procedure similar to that described for 8k, 3.23 g (0.007 mol) of 7l was converted to 1.58 g (47%) of 8l as a beige solid: 1H NMR (CDCl3) δ 12.23 (bs, 1H), 7.53 (d, 2H, J ) 8.4 Hz), 7.38 (d, 2H, J ) 8.4 Hz), 7.02 (d, 2H, J ) 8.5 Hz), 6.91 (d, 2H, J ) 8.5 Hz), 4.17 (m, 2H), 3.97 (m, 3H), 3.75 (d, 1H), 3.43 (m, 1H), 3.29 (m, 1H), 3.21 (m, 1H), 3.10 (m, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.10 (m, 3H), 1.73 (m, 2H), 1.58 (m, 1H); 13C NMR (CDCl3) δ 129.23, 128.98, 128.29, 127.99, 65.55, 65.44, 62.06, 61.41, 53.75, 41.27, 36.59, 35.61, 26.57, 25.42, 21.52; LCMS (ESI) m/z 472.1 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(4-chlorophenyl)thiazol-2-yl]tropane (4l) Hydrochloride. Compound 8l was cyclized using a procedure similar to that described for 4k to give 750 mg of 4l free base, which was converted to 739 mg (89%) of the hydrochloride salt as an off-white powder: 1H NMR (CDCl3 free base) δ 7.57 (s, 1H), 7.49 (d, 2H, J ) 8.4 Hz), 7.34 (d, 2H, J ) 8.4 Hz), 6.92 (d, 2H, J ) 8.4 Hz), 6.76 (d, 2H, J ) 8.4 Hz), 3.51 (m, 1H), 3.39 (m, 1H), 3.29 (m, 1H), 3.24 (t, 1H), 2.38 (m, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 2.19 (m, 2H), 1.84 (m, 2H), 1.65 (m, 1H); 13C NMR (CDCl3) δ 136.82, 129.40, 129.19, 128.04, 127.95, 66.22, 62.14, 53.58, 42.15, 37.39, 35.53, 26.39, 25.97, 21.40; LCMS (ESI) m/z 446.5 (M + 1)+. The hydrochloride salt had a mp of 192195 °C; [R]20D -22.5° (c 0.20, CH3OH). Anal. (C24H26Cl2N2S‚ 0.5H2O) C, H, N, S. 3β-(4-Methylphenyl)tropane-2β-N-3′-bromophenylacylcarboxamide Ethylene Ketal (7n). Using a procedure similar to that described for 7k, 5b (1 mmol) was coupled to 260 mg (1 mmol) of 12e to give 255 mg (52%) of 7n as a white solid: 1H NMR (CDCl3) δ 9.88 (bt, 1H), 7.73 (dd, 1H, J ) 1.8 Hz), 7.49-7.46 (m, 2H, J ) 8.1 Hz), 7.28 (d, 1H, J ) 8.1 Hz), 6.99 (d, 2H, J ) 8.1 Hz), 6.91 (d, 2H, J ) 8.1 Hz), 4.12 (m, 2H), 3.92 (m, 2H), 3.58 (m, 2H), 3.27 (m, 2H), 3.00 (m, 1H), 2.44 (dd, 1H), 2.26 (s, 3H), 2.21 (s, 3H), 2.13 (m, 3H), 1.74-1.55 (m, 3H); 13C NMR (CDCl3) δ 131.91, 130.35, 129.77, 129.32, 128.00, 125.26, 65.53, 65.40, 64.29, 61.82, 54.84, 46.96, 41.44, 35.95, 35.61, 26.49, 25.39, 21.49; LCMS (ESI) m/z 499.6 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-3′-bromophenylacylcarboxthioamine Ethylene Ketal (8n). Using a procedure similar to that described for 8k, 268 mg (0.54 mmol) of 7n was converted to 107 mg (68%) of 8n as a tan solid: 1H NMR (CDCl3) δ 12.23 (bs, 1H), 7.78 (d, 1H, J ) 1.8 Hz), 7.51 (m, 2H), 7.30 (dd, 1H, J ) 7.8 Hz), 7.00 (d, 2H, J ) 8.1 Hz), 6.82 (d, 2H, J ) 8.1 Hz), 4.16 (m, 2H), 3.97 (m, 3H), 3.72 (dd, 1H), 3.42 (m, 1H), 3.32 (m, 1H), 3.16 (dd, 1H), 3.00 (m, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.12 (m, 3H), 1.75 (m, 2H), 1.57 (m, 1H); 13C NMR (CDCl3) δ 131.89, 130.17, 129.29, 128.83, 127.86, 124.86, 65.19, 65.13, 61.62, 61.07, 53.83, 40.87, 36.16, 35.13, 26.16, 25.06, 21.11; LCMS (ESI) m/z 515.7 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(3′-bromophenyl)thiazol-2-yl]tropane (4n) Hydrochloride. Using a procedure similar to that described for 4k, 107 mg (0.208 mmol) of 8n was cyclized to give 64 mg (67%) of 4n free base: 1H NMR (CDCl3) δ 7.72 (dd, 1H, J ) 1.8 Hz), 7.58 (s, 1H), 7.50 (dd, 1H, J ) 1.8, 7.8 Hz), 7.38 (dd, 1H, J ) 7.8 Hz), 7.22 (dd, 2H, J ) 8.1 Hz), 6.92 (d, 2H, J ) 8.1 Hz), 6.72 (d, 2H, J ) 8.1 Hz), 3.51 (m, 1H), 3.38 (m, 1H), 3.25 (m, 2H), 2.43 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.17 (m, 2H), 1.83 (m 2H), 1.59 (m, 1H); 13C NMR (CDCl3) δ 137.20, 130.72, 130.69, 129.67, 129.21, 127.93, 125.38, 66.19, 62.14, 53.62, 42.17, 37.41, 35.50, 26.39, 25.99, 21.40; LCMS (ESI) m/z 453.0 (M + 1)+. The hydrochloride salt had a mp of 223-224 °C; [R]20D -20.0° (c 0.20, CH3OH). Anal. (C24H26BrClN2S) C, H, N, S. 3β-(4-Methylphenyl)tropane-2β-N-4-nitrophenacylcarboxamide Ethylene Ketal (7o). Using a procedure similar to that described for 7k, 260 mg (1 mmol) of 5b was coupled to 225 mg (1 mmol) of 12c to give 415 mg (89%) of 7o as a white solid: 1H NMR (CDCl3) δ 9.92 (bt, 1H), 8.21 (d, 2H, J ) 9.3 Hz), 7.72 (d, 2H, J ) 9.3 Hz), 7.01 (d, 2H, J ) 8.4 Hz), 6.95 (d, 2H, J ) 8.4

Gong et al.

Hz), 4.15 (m, 2H), 3.89 (m, 2H), 3.60 (dd, 2H), 3.25 (m, 2H), 3.00 (m, 1H), 2.47 (d, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.15 (m, 3H), 1.72-1.66 (m, 3H); 13C NMR (CDCl3) δ 129.33, 127.88, 127.68, 123.79, 65.75, 65.56, 64.34, 61.85, 54.73, 46.31, 41.57, 35.96, 35.42, 26.49, 25.36, 21.47; LCMS (ESI) m/z 466.7 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-4-nitrophenacylthiocarboxthioamide Ethylene Ketal (8o). Using a procedure similar to that described for 8k, 328 mg (0.70 mmol) of 7o was converted to 163 mg (48%) of 8o as a tan solid: 1H NMR (CDCl3) δ 12.30 (bs, 1H), 8.26 (d, 2H, J ) 9.3 Hz), 7.77 (d, 2H, J ) 9.3 Hz), 7.02 (d, 2H, J ) 8.4 Hz), 6.91 (d, 2H, J ) 8.4 Hz), 4.23 (m, 2H), 3.98 (m, 3H), 3.86 (m, 1H), 3.45 (m, 1H), 3.33 (m, 1H), 3.24 (m, 1H), 3.15 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.21 (m, 3H), 1.70-1.56 (m, 3H); 13C NMR (CDCl3) δ 129.24, 128.19, 127.70, 124.04, 65.67, 65.57, 62.06, 61.43, 53.36, 41.37, 35.53, 35.66, 26.59, 25.42, 21.51; LCMS (ESI) m/z 482.6 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(4′-nitrophenyl)thiazol-2-yl]tropane (4o) Hydrochloride. Using a procedure similar to that described for 4k, 144 mg (0.30 mmol) of 8o was cyclized to give 122 mg (97%) of 4o free base, which was converted to the hydrochloride salt: 1H NMR (CDCl3 free base) δ 8.15 (d, 2H, J ) 9.3 Hz), 7.65 (d, 2H, J ) 9.3 Hz), 7.62 (s, 1H), 6.85 (d, 2H, J ) 8.4 Hz), 6.69 (d, 2H, J ) 8.4 Hz), 3.48 (m, 1H), 3.34 (m, 1H), 3.22 (m, 2H), 2.35 (m, 1H), 2.29 (s, 3H), 2.11 (s, 3H), 2.10 (m, 2H), 1.60 (m, 2H), 1.56 (m, 1H); 13C NMR (CDCl3) δ 137.49, 127.80, 126.43, 125.58, 123.30, 64.67, 60.67, 52.23, 40.72, 35.91, 33.89, 24.92, 24.57, 19.97; LCMS (ESI) m/z 420.8 (M + 1)+. The hydrochloride salt had a mp of 170-176 °C; [R]20D -16.5° (c 0.20, CH3OH). Anal. (C24H26ClN3O2S‚2.5H2O) C, H, N, S. 3β-(4-Methylphenyl)tropane-2β-N-3-nitrophenacylcarboxamide Ethylene Ketal (7p). Using a procedure similar to that described for 8k, 244 mg (1.09 mmol) of 5b was coupled with 12f to give 318 mg (63%) of 7p as a white solid: 1H NMR (CDCl3) δ 9.99 (bt, 1H), 8.43 (s, 1H), 8.18 (d, 1H, J ) 8.1 Hz), 7.87 (d, 1H, J ) 8.1 Hz), 7.56 (dd, 1H, J ) 8.1 Hz), 7.99 (d, 2H, J ) 8.1 Hz), 6.90 (d, 2H, J ) 8.1 Hz), 4.16 (m, 2H), 3.92 (m, 2H), 3.68 (dd, 1H), 3.58 (dd, 1H), 3.28 (m, 1H), 3.21 (m, 1H), 3.00 (m, 1H), 2.42 (dd, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 2.12 (m, 3H), 1.72 (m, 2H), 1.61 (dt, 1H); 13C NMR (CDCl3) δ 132.90, 129.80, 129.32, 127.87, 123.90, 121.71, 65.74, 65.61, 64.25, 61.82, 54.70, 46.63, 41.48, 35.89, 35.43, 26.48, 25.36, 21.47; LCMS (ESI) m/z 466.7 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-(3-nitrophenacyl)carboxthioamide Ethylene Ketal (8p). Using a procedure similar to that described for 8k, 303 mg (0.70 mmol) of 7p was converted to 141 mg (45%) of 8p as a tan solid: 1H NMR (CDCl3) δ 9.99 (bt, 1H), 8.49 (dd, 1H, J ) 1.8 Hz), 8.25 (dd, 1H, J ) 1.8, 8.4 Hz), 7.94 (dd, 1H, J ) 1.8, 8.4 Hz), 7.62 (dd, 1H, J ) 8.4 Hz), 7.99 (d, 2H, J ) 8.4 Hz), 6.83 (d, 2H, J ) 8.4 Hz), 4.23 (m, 2H), 3.99 (m, 2H), 3.85 (d, 1H), 3.80 (d, 1H), 3.45 (d, 1H), 3.31 (m, 1H), 3.19 (m, 1H), 3.07 (m, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 2.14 (m, 3H), 1.76 (m, 2H), 1.61 (dt, 1H); 13C NMR (CDCl3) δ 132.81, 130.09, 129.22, 128.15, 124.24, 121.65, 65.76, 65.11, 65.61, 62.03, 61.38, 53.79, 41.26, 36.46, 35.54, 26.51, 25.41, 21.48; LCMS (ESI) m/z 482.6 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(3-nitrophenyl)thiazol-2-yl]tropane (4p) Hydrochloride. Using a procedure similar to that described for 4k, 132 mg (0.274 mmol) of 8p was cyclized to give 88 mg (76%) of 4p free base, which yielded 65 mg (65%) of the hydrochloride salt as a white solid: 1H NMR (CDCl3 free base) δ 8.41 (s, 1H), 8.12 (dd, 1H, J ) 1.8, 7.5 Hz), 7.88 (d, 1H, J ) 7.5 Hz), 7.70 (s, 1H), 7.54 (dd, 1H, J ) 7.5 Hz), 6.94 (d, 2H, J ) 8.1 Hz), 6.77 (d, 2H, J ) 8.1 Hz), 3.54 (m, 1H), 3.42 (m, 1H), 3.30 (m, 1H), 3.26 (m, 1H), 2.43 (s, 3H), 2.29 (m, 3H), 2.23 (s, 3H), 1.85 (m, 2H), 1.64 (dt, 1H); 13C NMR (CDCl3) δ 138.03, 132.42, 130.19, 129.24, 127.89, 122.33, 121.49, 66.15, 62.13, 53.64, 42.17, 37.35, 35.36, 26.37, 26.00, 21.40; LCMS (ESI) m/z 420.9 (M + 1)+. The hydrochloride salt had a mp of 208-211 °C; [R]20D -10.5° (c 0.20, CH3OH). Anal. (C24H26ClN3O2S‚1H2O) C, H, N, S. 3β-(4-Methylphenyl)tropane-2β-N-4-methoxyphenacyl)carboxamide Ethylene Ketal (7q). Using a procedure similar to that


described for 7k, 250 mg (1 mmol) of 5b was coupled with 250 mg (1 mmol) of 12d to give 286 mg (53%) of 7q as a clear oil: 1H NMR (CDCl ) δ 9.87 (bt, 1H), 7.47 (d, 2H, J ) 8.1 Hz), 7.02 3 (d, 2H, J ) 8.1 Hz), 6.98 (d, 2H, J ) 8.1 Hz), 6.89 (d, 2H, J ) 8.1 Hz), 4.11 (m, 2H), 3.92 (m, 2H), 3.81 (s, 3H), 3.59 (d, 2H, J ) 5.1 Hz), 3.24 (m, 2H), 3.00 (m, 1H), 2.44 (dd, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 2.15 (m, 3H), 1.70 (m, 2H), 1.60 (dt, 1H); 13C NMR (CDCl3) δ 129.33, 128.10, 127.76, 113.93, 65.37, 65.19, 64.31, 61.85, 55.71, 54.90, 46.77, 41.49, 36.08, 35.71, 26.53, 25.38, 21.50; LCMS (ESI) m/z 451.5 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-(4-methoxyphenacyl)carboxthioamide Ethylene Ketal (8q). Using a procedure similar to that described for 8k, 280 mg (0.62 mmol) of 7q was converted to 83 mg (29%) of 8q as a tan solid: 1H NMR (CDCl3) δ 12.14 (bs, 1H), 7.50 (d, 2H, J ) 8.1 Hz), 7.02 (d, 2H, J ) 8.1 Hz), 6.92 (d, 4H, J ) 8.4 Hz), 4.14 (m, 2H), 3.96 (m, 3H), 3.81 (s, 3H), 3.75 (d, 1H), 3.44 (d, 1H), 3.28 (m, 1H), 3.20 (dd, 1H), 3.09 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 2.14 (m, 3H), 1.72 (m, 2H), 1.57 (dt, 1H); 13C NMR (CDCl ) δ 129.21, 128.35, 127.76, 114.11, 65.57, 65.32, 3 65.27, 62.09, 61.32, 55.77, 53.98, 41.23, 36.62, 35.56, 26.55, 25.41, 21.51; LCMS (ESI) m/z 467.6 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(4-methoxyphenyl)thiazol-2-yl]tropane (4q) Hydrochloride. Using a procedure similar to that described for 4k, 110 mg (0.24 mmol) of 8q was cyclized to give 72 mg (75%) of 4q free base, which was converted to the hydrochloride salt: 1H NMR (CDCl3) δ 7.50 (d, 2H J ) 8.7 Hz), 7.49 (s, 1H), 6.92 (d, 2H, J ) 8.1 Hz), 6.89 (d, 2H, J ) 8.1 Hz), 6.77 (d, 2H, J ) 8.1 Hz), 3.83 (s, 3H), 3.49 (m, 1H), 3.38 (m, 1H), 3.30 (m, 1H), 3.22 (m, 1H), 2.41 (m, 1H), 2.33 (s, 3H), 2.25 (m, 2H), 2.21 (s, 3H), 1.83 (m, 2H), 1.60 (m, 1H); 13C NMR (CDCl3) δ 135.55, 129.15, 128.13, 128.01, 114.72, 66.31, 62.18, 55.79, 53.55, 42.15, 37.46, 35.69, 26.42, 25.95, 21.39; LCMS (ESI) m/z 405.7 (M + 1)+. The hydrochloride salt had a mp of 155-160 °C; [R]20D -14.5° (c 0.20, CH3OH). Anal. (C25H30ClN2OS‚1.5H2O) C, H, N, S. 3β-(4-Methylphenyl)tropane-2β-N-(3,4-dichlorophenacyl)carboxamide Ethylene Ketal (7r). Using a procedure similar to that described for 7k, 1.04 g (0.004 mol) of 5b was coupled with 1.0 g (0.004 mol) of 12g to give 1.33 g (67%) of 7r as a white powder: 1H NMR (CDCl ) δ 9.86 (bt, 1H), 7.66 (d, 1H, J ) 1.8 Hz), 7.45 3 (d, 1H, J ) 8.1 Hz), 7.36 (d, 1H, J ) 8.1 Hz), 7.01 (d, 2H, J ) 8.4 Hz), 6.95 (d, 2H, J ) 8.4 Hz), 4.10 (m, 2H), 3.91 (m, 2H), 3.57 (d, 2H, J ) 5.4 Hz), 3.29 (m, 1H), 3.23 (m, 1H), 3.03 (m, 1H), 2.45 (dd, 1H, J ) 6.9 Hz), 2.26 (s, 3H), 2.21 (s, 3H), 2.15 (m, 3H), 1.65 (m, 3H); 13C NMR (CDCl3) δ 130.77, 129.34, 128.81, 127.94, 126.08, 65.62, 65.46, 64.30, 61.83, 54.78, 46.65, 41.47, 35.91, 35.51, 26.91, 25.37, 21.51; LCMS (ESI) m/z 489.3 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-(3,4-dichlorophenacyl)carboxthioamide Ethylene Ketal (8r). Using a procedure similar to that described for 8k, 977 mg (2.0 mmol) of 7r was converted to 597 mg (59%) of 8r as a beige crystalline powder: 1H NMR (CDCl3) δ 12.24 (bs, 1H), 7.71 (d, 1H, J ) 1.8 Hz), 7.49 (d, 1H, J ) 8.4 Hz), 7.41 (dd, 1H, J ) 2.1 Hz, 8.4 Hz), 7.02 (d, 2H, J ) 7.8 Hz), 6.87 (d, 2H, J ) 7.8 Hz), 4.17 (m, 2H), 3.95 (m, 3H), 3.75 (dd, 1H, J ) 15 Hz), 3.42 (m, 1H), 3.32 (m, 1H), 3.21 (m, 1H), 3.08 (m, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.15 (m, 3H), 1.68 (m, 3H); 13C NMR (CDCl3) δ 130.57, 128.82, 128.33, 127.80, 125.62, 65.19, 65.17, 65.13, 61.61, 61.03, 53.42, 40.86, 36.11, 35.13, 26.14, 26.02, 21.09; LCMS (ESI) m/z 505.6 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(3,4-dichlorophenyl)thiazol-2-yl]tropane (4r) Hydrochloride. Using a procedure similar to that described for 4k, 567 mg (1.18 mmol) of 8r was cyclized to give 505 mg of 4r free base, which was converted to 410 mg (75%) of the hydrochloride salt: 1H NMR (CDCl3 free base) δ 7.65 (d, 1H, J ) 1.5 Hz), 7.56 (s, 1H), 7.40 (m, 2H), 6.92 (d, 2H, J ) 8.1 Hz), 6.75 (d, 2H, J ) 8.1 Hz), 3.51 (m, 1H), 3.39 (m, 1H), 3.25 (m, 2H), 2.42 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.19 (m, 2H), 1.84 (m, 2H), 1.64 (m, 1H); 13C NMR (CDCl3) δ 137.43, 131.11, 129.21, 128.43, 127.90, 125.95, 66.16, 62.13, 53.60, 42.16, 37.37, 35.43, 26.37, 25.99, 21.40; LCMS (ESI) m/z 443.8 (M + 1)+. The


hydrochloride salt had a mp of 214-216 °C; [R]20D -13.0° (c 0.20, CH3OH). Anal. (C24H25Cl3N2S) C, H, N, S. 3β-(4-Methylphenyl)tropane-2β-N-3,4-dimethoxyphenacylcarboxamide Ethylene Ketal (7s). Using a procedure similar to that described for 7k, 893 mg (3.44 mmol) of 5b was coupled to 825 mg (3.44 mmol) of 12h to give 1.42 g (86%) of 7s as a clear viscous oil: 1H NMR (CDCl3) δ 9.86 (bt, 1H), 7.11 (dd, 1H, J ) 2.1, 8.1 Hz), 7.05 (d, 1H, J ) 2.1 Hz), 6.99 (d, 2H, J ) 9 Hz), 6.98 (d, 2H, J ) 9 Hz), 6.86 (d, 1H, J ) 8.1 Hz), 4.10 (m, 2H), 3.94 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.61 (d, 2H, J ) 5.1 Hz), 3.25 (m, 2H), 3.03 (m, 1H), 2.46 (dd, 1H, J ) 6.6 Hz), 2.26 (s, 3H), 2.15 (s, 3H), 2.10 (m, 3H), 1.70 (m, 3H); 13C NMR (CDCl3) δ 129.32, 128.08, 118.85, 111.11, 109.69, 65.44, 65.22, 65.36, 61.87, 56.37, 54.91, 46.61, 41.51, 36.12, 35.68, 26.53, 25.37, 21.50; LCMS (ESI) m/z 481.5 (M + 1)+. 3β-(4-Methylphenyl)tropane-2β-N-3,4-dimethoxyphenacylcarboxthioamide Ethylene Ketal (8s). Using a procedure similar to that described for 4k, 1.05 g (0.0021 mol) of 7s was converted to 520 mg (47%) of 8s as a tan crystalline solid: 1H NMR (CDCl3) δ 12.21 (bs, 1H), 7.15 (dd, 1H, J ) 2.1, 8.1 Hz), 7.08 (d, 1H, J ) 2.1 Hz), 7.02 (d, 2H, J ) 7.8 Hz), 6.95 (d, 2H, J ) 7.8 Hz), 6.90 (d, 1H, J ) 8.1 Hz), 4.16 (m, 2H), 3.99 (m, 2H), 3.98 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.81 (d, 1H), 3.43 (d, 1H), 3.27 (m, 1H), 3.20 (m, 1H), 3.09 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 2.10 (m, 3H), 1.70 (m, 2H), 1.60 (m, 1H); 13C NMR (CDCl3) δ 129.92, 129.05, 119.62, 111.196, 110.37, 66.27, 66.09, 66.04, 62.80, 62.21, 57.16, 54.59, 42.02, 37.35, 36.35, 27.30, 26.14, 22.23; LCMS (ESI) m/z 497.8 (M + 1)+. 3β-(4-Methylphenyl)-2β-[5-(3,4-dimethoxyphenyl)thiazol-2-yl]tropane (4s) Dihydrochloride. Using a procedure similar to that described for 4k, 520 mg (1.03 mmol) of 8s was cyclized to 450 mg of 4s free base, which was converted to 450 mg (82%) of the dihydrochloride salt: 1H NMR (CDCl3 free base) δ 7.50 (s, 1H), 7.14 (dd, 1H, J ) 2.1, 8.1 Hz), 7.05 (d, 1H, J ) 2.1 Hz), 6.92 (d, 2H, J ) 7.8 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 6.77 (d, 2H, J ) 7.8 Hz), 3.95 (s, 3H), 3.90 (s, 3H), 3.50 (m, 1H), 3.39 (m, 1H), 3.31 (m, 1H), 3.23 (m, 1H), 2.42 (m, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 2.16 (m, 2H), 1.82 (m, 2H), 1.63 (m, 1H); 13C NMR (CDCl3) δ 135.72, 129.17, 128.02, 119.61, 111.99, 110.31, 66.31, 62.17, 56.51, 56.45, 53.56, 42.17, 37.45, 35.70, 26.43, 25.85, 21.40; LCMS (ESI) m/z 435.7 (M + 1)+. The dihydrochloride salt had a mp of 140148 °C; [R]20D -7.5° (c 0.20, CH3OH). Anal. (C25H32Cl2N2O2S‚ 1.25H2O) C, H, N, S. 3β-(4-Chlorophenyl)tropane-2β-N-3-bromophenacylcarboxamide Ethylene Ketal (7e). Using a procedure similar to that described for 7k, 279 mg (1 mmol) of 5a was coupled with 259 mg (1 mmol) of 12e to give 145 mg (28%) of 7e as a white solid: 1H NMR (CDCl ) δ 9.89 (bt, 1H), 7.73 (dd, 1H, J ) 1.8 Hz), 7.48 3 (dd, 2H, J ) 1.8, 7.8 Hz), 7.28 (dd, 1H, J ) 7.8 Hz), 7.14 (d, 2H, J ) 8.4 Hz), 6.95 (d, 2H, J ) 8.4 Hz), 4.11 (m, 2H), 3.91 (m, 2H) 3.65 (dd, 1H), 3.55 (dd, 1H), 3.30 (m, 1H), 3.24 (dd, 1H), 3.00 (m, 1H), 2.43 (dd, 1H), 2.20 (s, 3H), 2.11 (m, 3H), 1.70-1.59 (m, 3H); 13C NMR (CDCl3) δ 131.96, 130.42, 129.76, 129.53, 128.69, 125.25, 65.53, 65.40, 64.19, 61.69, 54.62, 47.00, 41.39, 35.85, 35.50, 26.46, 25.35; LCMS (ESI) m/z 521.7 (M + 1)+. 3β-(4-Chlorophenyl)tropane-2β-N-3-bromophenacylcarboxthioamide Ethylene Ketal (8e). Using a procedure similar to that described for 8k, 140 mg (0.270 mmol) of 7e was converted to 61 mg (42%) of 8e as a tan solid: 1H NMR (CDCl3) δ 12.23 (bs, 1H), 7.77 (dd, 1H), 7.51 (dd, 2H, J ) 1.5, 7.8 Hz), 7.31 (dd, 1H J ) 7.8 Hz), 7.16 (d, 2H, J ) 8.4 Hz), 6.86 (d, 2H, J ) 8.4 Hz), 4.16 (m, 2H), 3.96 (m, 3H), 3.67 (d, 1H), 3.43 (d, 1H), 3.33 (m, 1H), 3.15 (d, 1H), 3.07 (m, 1H), 2.23 (s, 3H), 2.08 (m, 3H), 1.741.55 (m, 3H); 13C NMR (CDCl3) δ 131.93, 130.22, 129.33, 129.26, 128.21, 124.84, 65.18, 65.13, 61.46, 60.81, 53.82, 40.80, 35.95, 35.92, 26.12, 25.00; LCMS (ESI) m/z 535.3 (M + 1)+. 3β-(4-Chlorophenyl)-2β-[5-(3-bromo-2-thiazol)-2-yl]tropane (4e) Hydrochloride. Using a procedure similar to that described for 4k, 61 mg (0.114 mmol) of 8e was cyclized to give 36 mg (67%) of 4e free base, which was converted to the hydrochloride salt as a tan solid: 1H NMR (CDCl3 free base) δ

3694


7.72 (dd, 1H), 7.59 (s, 1H), 7.50 (dd, 1H, J ) 1.5, 6.9 Hz), 7.41(d, 1H, J ) 1.5, 6.9 Hz), 7.21 (dd, 1H, J ) 7.8 Hz), 7.08 (d, 2H, J ) 8.4 Hz), 6.80 (d, 2H, J ) 8.4 Hz), 3.50 (dd, 1H), 3.40 (m, 1H), 3.31 (t, 1H), 3.24 (t, 1H), 2.35 (s, 3H), 2.23 (m, 3H), 1.82 (m, 2H), 1.64 (dt, 1H); 13C NMR (CDCl3) δ 137.24, 130.83, 130.76, 129.71, 129.41, 128.58, 125.36, 66.08, 62.00, 53.39, 42.13, 37.27, 35.32, 26.38, 25.93; LCMS (ESI) m/z 475.8 (M + 1)+. The hydrochloride salt had a mp of 185-200 °C; [R]20D -26.5° (c 0.20, CH3OH). Anal. (C23H23BrCl2N2S‚2.0H2O) C, H, N, S. 3β-(4-Chlorophenyl)tropane-2β-N-(3-nitrophenacyl)carboxamide Ethylene Ketal (7g). Using a procedure similar to that described for 7k, 321 mg (1.15 mmol) of 5a was coupled with 257 mg (1.15 mmol) of 12f to give 128 mg (23%) of 7g as a white solid: 1H NMR (CDCl3) δ 9.98 (bt, 1H), 8.42 (dd, 1H, J ) 2.1 Hz), 8.20 (dd, 1H, J ) 2.1, 7.5 Hz), 7.87 (dd, 1H, J ) 2.1, 7.5 Hz), 7.56 (dd, 1H, J ) 7.5 Hz), 7.14 (d, 1H, J ) 8.7 Hz), 6.97 (d, 2H, J ) 8.7 Hz), 4.16 (m, 2H), 3.92 (m, 2H) 3.64 (dd, 1H), 3.56 (dd, 1H), 3.29 (m, 1H), 3.23 (dd, 1H), 3.00 (m, 1H), 2.43 (dd, 1H), 2.25 (s, 3H), 2.14 (m, 3H), 1.67 (m, 3H); LCMS (ESI) m/z 486.5 (M + 1)+. 3β-(4-Chlorophenyl)tropane-2β-N-(3-nitrophenacyl)carboxthioamide Ethylene Ketal (8g). Using a procedure similar to that described for 8k, 256 mg (0.53 mmol) of 7g was converted to 155 mg (54%) of 8g as a tan solid: 1H NMR (CDCl3) δ 12.34 (bs, 1H), 8.48 (dd, 1H, J ) 2.1 Hz), 8.25 (dd, 1H, J ) 2.1, 7.5 Hz), 7.91 (dd, 1H, J ) 2.1, 7.5 Hz), 7.62 (dd, 1H, J ) 7.8 Hz), 7.15 (d, 2H, J ) 8.1 Hz), 6.89 (d, 2H, J ) 8.1 Hz), 4.22 (m, 2H), 3.97 (m, 3H), 3.82 (d, 1H), 3.44 (d, 1H), 3.31 (m, 1H), 3.18 (d, 1H), 3.10 (m, 1H), 2.27 (s, 3H), 2.10 (m, 3H), 1.75 (m, 2H), 1.54 (m, 1H); 13C NMR (CDCl ) δ 132.82, 130.16, 129.63, 128.60, 124.28, 3 121.61, 65.74, 65.72, 65.46, 61.86, 61.17, 53.76, 41.25, 36.31, 35.42, 26.52, 25.37; LCMS (ESI) m/z 503.0 (M + 1)+. 3β-(4-Chlorophenyl)-2β-[5-(3-nitrophenylthiazol)-2-yl]tropane (4g) Hydrochloride. Using a procedure similar to that described for 4k, 155 mg (0.31 mmol) of 8g was cyclized to give 104 mg (76%) of 4g free base, which was converted to the hydrochloride salt as a tan solid: 1H NMR (CDCl3 free base) δ 8.41 (dd, 1H, J ) 1.8 Hz), 8.13 (dd, 1H, J ) 1.8 Hz), 7.89 (dd, 1H, J ) 1.8, 8.4 Hz), 7.70 (s, 1H, J ) 7.5 Hz), 7.57 (dd, 1H, J ) 7.5 Hz), 7.10 (d, 2H, J ) 6.9 Hz), 6.82 (d, 2H, J ) 6.9 Hz), 3.54 (dd, 1H), 3.43 (m, 1H), 3.31 (m, 1H), 3.27 (t, 1H), 2.37 (s, 3H), 2.22 (m, 3H), 1.85 (m, 2H), 1.65 (m, 1H); 13C NMR (CDCl3) δ 138.06, 132.36, 130.24, 129.37, 127.62, 122.45, 121.55, 66.03, 61.98, 53.42, 42.15, 37.19, 35.18, 26.36, 25.95; LCMS (ESI) m/z 440.6 (M + 1)+. The hydrochloride salt had a mp of 160-162 °C; [R]20D -25.5° (c 0.20, CH3OH). Anal. (C23H24Cl3N3O2S‚1.5H2O) C, H, N, S. 3β-(4-Chlorophenyl)tropane-2β-N-(3,4-dichlorophenacyl)carboxamide Ethylene Ketal (7i). Using a procedure similar to that described for 7k, 1.19 g (0.0043 mol) of 5a was coupled with 1.04 g (0.0043 mol) of 12g to give 0.83 g (39%) of 7i as a white powder: 1H NMR (CDCl3) δ 9.88 (bt, 1H), 7.65 (d, 1H, J ) 1.8 Hz), 7.46 (d, 1H, J ) 8.1 Hz), 7.36 (dd, 1H, J ) 2.1 Hz, 8.1 Hz), 7.17 (d, 2H, J ) 8.4 Hz), 7.00 (d, 2H, J ) 8.4 Hz), 4.12 (m, 2H), 3.90 (m, 2H), 3.58 (m, 2H), 3.29 (m, 1H), 3.24 (m, 1H), 3.03 (m, 1H), 2.45 (dd, 1H, J ) 9 Hz), 2.21 (s, 3H), 2.13 (m, 3H), 1.65 (m, 3H); 13C NMR (CDCl3) δ 130.45, 129.10, 128.42, 128.33, 125.68, 65.23, 65.07, 63.83, 61.32, 54.19, 46.28, 41.03, 35.46, 35.04, 26.08, 24.96; LCMS (ESI) m/z 511.3 (M + 1)+. 3β-(4-Chlorophenyl)tropane-2β-N-(3,4-dichlorophenacyl)carboxthioamide Ethylene Ketal (8i). Using a procedure similar to that described for 8k, 835 mg (1.64 mmol) of 7i was converted to 366 mg (42%) of 8i as a beige crystalline solid: 1H NMR (CDCl3) δ 12.22 (bs, 1H), 7.70 (d, 1H, J ) 1.8 Hz), 7.50 (d, 1H, J ) 8.1 Hz), 7.41 (dd, 1H, J ) 1.8, 8.1 Hz), 7.16 (d, 2H, J ) 8.4 Hz), 6.92 (d, 2H, J ) 8.4 Hz), 4.17 (m, 2H), 3.9 (m, 3H), 3.72 (dd, 1H, J ) 2.4, 15 Hz), 3.43 (bd, 1H), 3.41 (m, 1H), 3.20 (bd, 1H), 3.10 (m, 1H), 2.22 (s, 3H), 2.10(m, 3H), 1.7 (m, 3H); 13C NMR (CDCl3) δ 131.03, 129.70, 128.71, 128.60, 126.01, 65.58, 65.43, 61.87, 61.21, 53.81, 41.21, 36.34, 35.37, 26.52, 25.38; LCMS (ESI) m/z 527.6 (M + 1)+.

Gong et al.

3β-(4-Chlorophenyl)-2β-[5-(3,4-dichlorophenyl)thiazol-2-yl]tropane (4i) Hydrochloride. Using a procedure similar to that described for 4k, 619 mg (1.18 mmol) of 8i was cyclized to give 501 mg (92%) of 4i free base, which was converted to the hydrochloride salt as a white solid: 1H NMR (CDCl3 free base) δ 7.65 (d, 1H, J ) 1.8 Hz), 7.58 (s, 1H), 7.42 (d, 1H, J ) 8.4 Hz), 7.38 (dd, 1H, J ) 1.8, 8.4 Hz), 7.08 (d, 2H, J ) 8.1 Hz), 6.79 (d, 2H, J ) 8.1 Hz), 3.51 (m, 1H), 3.40 (m, 1H), 3.29 (m, 1H), 3.25 (m, 1H), 2.38 (m, 1H), 2.35 (s, 3H), 2.21 (m, 2H), 1.83 (m, 2H), 1.63(m, 1H); 13C NMR (CDCl3) δ 25.93, 26.37, 35.25, 37.22, 42.12, 53.38, 61.98, 66.04, 125.93, 128.46, 128.60, 129.39, 131.16, 137.48; LCMS (ESI) m/z 465.4 (M + 1)+. The hydrochloride salt had a mp of 164-172 °C; [R]20D -20.5° (c 0.20, CH3OH). Anal. (C23H22Cl4N2S‚2.25H2O) C, H, N, S. 3β-(4-Chlorophenyl)tropane-2β-N-(3,4-dimethoxyphenacyl)carboxamide Ethylene Ketal (7j). Using a procedure similar to that described for 7k, 1.19 g (0.0043 mol) of 5a was coupled to 1.02 g (0.0043 mol) of 12h to give 1.16 g (55%) of 7j as a white solid: 1H NMR (CDCl3) δ 9.80 (bt, 1H), 7.17 (d, 2H, J ) 8.4 Hz), 7.12 (dd, 1H, J ) 1.8, 8.4 Hz), 7.05 (d, 2H, J ) 8.4 Hz), 7.03 (d, 1H, J ) 8.4 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 4.10 (m, 2H), 3.95 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.63 (dq, 2H), 3.26 (d, 2H), 3.03 (m, 1H), 2.46 (dd, 1H), 2.21 (s, 3H), 2.10 (m, 3H), 1.70 (m, 3H); 13C NMR (CDCl ) δ 129.21, 128.28, 118.43, 110.68, 109.18, 65.02, 3 64.81, 63.83, 61.31, 55.97, 54.25, 46.24, 41.06, 35.60, 35.16, 26.08, 24.92; LCMS (ESI) m/z 501.8 (M + 1)+. 3β-(4-Chlorophenyl)tropane-2β-N-(3,4-dimethoxyphenacyl)carboxthioamide Ethylene Ketal (8j). Using a procedure similar to that described for 8k, 1.16 g (0.0023 mol) of 7j was converted to 617 mg (51%) 8j as a tan solid: 1H NMR (CDCl3) δ 12.20 (bs, 1H), 7.17 (d, 2H, J ) 8.4 Hz), 7.08 (dd, 1H, J ) 1.8, 8.4 Hz), 7.07 (d, 1H, J ) 1.8 Hz), 6.97 (d, 2H, J ) 8.4 Hz), 6.90 (d, 1H, J ) 8.4 Hz), 4.15 (m, 2H), 3.01 (m, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.77 (dd, 1H), 3.44 (d, 1H), 3.28 (m, 1H), 3.19 (m, 1H), 3.10 (m, 1H), 2.21 (s, 3H), 2.10 (m, 3H), 1.71 (m, 2H), 1.56 (m, 1H); 13C NMR (CDCl3) δ 129.83, 128.57, 118.89, 111.27, 109.62, 65.43, 65.36, 65.34, 61.93, 61.26, 56.45, 53.89, 41.27, 36.45, 35.47, 26.57, 25.37; LCMS (ESI) m/z 517.7 (M + 1)+. 3β-(4-Chlorophenyl)-2β-[5-(3,4-dimethoxyphenyl)thiazol-2-yl]tropane (4j) Hydrochloride. Using a procedure similar to that described for 4k, 620 mg (1.2 mmol) of 8j was cyclized to give 515 mg (96%) of 4j free base, which was converted to the hydrochloride salt: 1H NMR (CDCl3, free base) δ 7.50 (s, 1H), 7.15 (dd, 1H, J ) 1.8, 8.4 Hz), 7.10 (d, 2H, J ) 8.4 Hz), 7.05 (d, 1H, J ) 1.8 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 6.83 (d, 2H, J ) 8.4 Hz), 3.95 (s, 3H), 3.91 (s, 3H), 3.50 (m, 1H), 3.40 (m, 1H), 3.31 (m, 1H), 3.24 (m, 1H), 2.36 (m, 1H), 2.35 (s, 3H), 2.23 (m, 2H), 1.65 (m, 2H), 1.60 (m, 1H); 13C NMR (CDCl3) δ 135.74, 129.50, 128.54, 119.64, 111.99, 110.24, 66.17, 62.02, 56.51, 56.45, 53.35, 42.14, 37.33, 35.49, 26.43, 25.91; LCMS (ESI) m/z 455.6 (M + 1)+. The hydrochloride salt had a mp of 159-168 °C; [R]20D -9.0° (c 0.20, CH3OH). Anal. (C25H28.5Cl2.5N2O2S‚1.75H2O) C, H, N, S.

Acknowledgment. This research was supported by the National Institute on Drug Abuse under projects DA05477 and DA-1-8815. We thank the NIDA (CTDP, Division of Pharmacotherapies and Medical Consequences of Drug Abuse) for the data in Table 2. Supporting Information Available: Elemental analysis. This material is available free of charge via the Internet at http:// pubs.acs.org.

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Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3695 (18) Kotian, P.; Abraham, P.; Lewin, A. H.; Mascarella, S. W.; Boja, J. W.; Kuhar, M. J.; Carroll, F. I. Synthesis and ligand binding study of 3β-(4′-substituted phenyl)-2β-(heterocyclic)tropanes. J. Med. Chem. 1995, 38, 3451-3453. (19) Kotian, P.; Mascarella, S. W.; Abraham, P.; Lewin, Anita H.; Boja , John W.; Kuhar, Michael J.; Carroll, F. I. Synthesis, ligand binding, and quantitative structure-activity relationship study of 3β-(4′substituted phenyl)-2β-(heterocyclic)tropanes: Evidence for an electrostatic interaction at the 2β-position. J. Med. Chem. 1996, 39, 2753-2763. (20) Carroll, F. I.; Howard, J. L.; Howell, L. L.; Fox, B. S.; Kuhar, M. J. Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse. AAPS J. 2006, 8, E196-203. (21) Carroll, F. I.; Fox, B. S.; Kuhar, M. J.; Howard, J. L.; Pollard, G. T.; Schenk, S. Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration. Eur. J. Pharmacol. 2006, 553, 149-156. (22) Howell, L. L.; Carroll, F. I.; Votaw, J. R.; Goodman, M. M.; Kimmel, H. L. Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys. J. Pharmacol. Exp. Ther. 2006, 320, 757-765. (23) Charette, A. B.; Chua, P. Thiolysis and hydrolysis of imino and iminium triflates: Synthesis of secondary and tertiary thioamides and O18-labelled amides. Tetrahedron Lett. 1998, 39, 245-248. (24) Staudinger, H.; Meyer, J. Synthesis of phosphazo compounds by the reaction of tertiary phosphines with organic azides. HelV. Chim. Acta 1919, 2, 635. (25) Boja, J. W.; Rahman, M. A.; Philip, A.; Lewin, A. H.; Carroll, F. I.; Kuhar, M. J. Isothiocyanate derivatives of cocaine: Irreversible inhibition of ligand binding at the dopamine transporter. Mol. Pharmacol. 1991, 39, 339-345. (26) Carroll, F. I.; Gray, J. L.; Abraham, P.; Kuzemko, M. A.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. 3-Aryl-2-(3′-substituted-1′,2′,4′oxadiazol-5′-yl)tropane analogues of cocaine: Affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters. J. Med. Chem. 1993, 36, 2886-2890. (27) Eshleman, A. J.; Carmolli, M.; Cumbay, M.; Martens, C. R.; Neve, K. A.; Janowsky, A. Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. J. Pharmacol. Exp. Ther. 1999, 289, 877-885.

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Synthesis, Monoamine Transporter Binding, Properties, and

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